New method

ABSTRACT

The invention provides a novel method of treating respiratory diseases, e.g., pediatric asthma, in a continuing regimen with not more than one daily dose of the drug budesonide using a nebulizer.

This application in a continuation of co-pending U.S. application Ser.No. 09/220,137, filed Dec. 23, 1998, which claims benefit of U.S.Provisional Application Ser. No. 60/070,291, filed Dec. 31, 1997. Thedisclosures of U.S. application Ser. No. 09/220,137 and U.S. ProvisionalApplication No. 60/070,291 are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

The invention relates to the treatment of respiratory diseases.

There is significant difficulty in the treatment of young children,including infants, who suffer from respiratory diseases, e.g., asthma.In light of the requirement for frequent and repeated administration ofappropriate drugs, issues of compliance and convenience are majoraspects of this problem. Furthermore, current methods of intrapulmonarydelivery of drugs, e.g., glucocorticosteroids (GCS), are not optimal foruse in infants and young children.

SUMMARY OF THE INVENTION

The invention provides a new method of treating respiratory diseasessuch as asthma that involves administering a budesonide composition witha nebulizer not more than once per day. This administration regimenimproves compliance and convenience, both significant factors intreating these diseases, particularly in infants and young children.Moreover, the nebulizer is readily and effectively used with infants aswell as young children.

Specifically, the invention features a method of treating a patientsuffering from a respiratory disease in which a composition, e.g., asuspension, of budesonide is administered by nebulization at a frequencyof between once per day and once per month in a continuing regimen. Forexample, the frequency of administration can be once and only once perday, or once and only once every two days. The doses can be, e.g., 0.05mg to 15 mg, 0.1 mg to 2.0 mg, or 0.25 mg to 1.0 mg budesonide. The drugcan be provided as an aqueous suspension in which the budesonide issuspended in a solvent containing about 0.05-mg to 0.15 mg sodiumedetate, about 8.0 mg to 9.0 mg sodium chloride, about 0.15 mg to 0.25mg polysorbate, about 0.25 mg to 0.30 mg anhydrous citric acid, andabout 0.45 mg to 0.55 mg sodium citrate per 1 ml of water.

This new method of treatment can be used in patients suffering fromrespiratory diseases that include, for example, inflammatory airwaydiseases, croup, and bronchopulmonary dysplasia. Inflammatory airwaydiseases include asthma, chronic obstructive pulmonary disease (COPD),and bronchiolitis. Patients can be any age from birth, e.g., newborn,one day to fifteen years old, one month to eight years old, or sixmonths to five years old. The method is also effective in olderpatients.

A “continuing regimen,” is a treatment regimen of a series of two ormore administrations that occur over days, weeks, months, or years. Thedosage of each administration can be the same or varied throughout thecontinuing regimen.

The doses of budesonide specified for administration by nebulization arethose added to the nebulizing device. In a typical situation,approximately 40% to 60% of the drug actually leaves the nebulizer, andof this only approximately 25% (i.e., 10% to 15% of the nominal dose) isdelivered to the patient. This is because the drug is deliveredconstantly, and when the patient is exhaling, the drug leaving thenebulizer will not be delivered to the patient; it will instead be lostto the environment. Of the amount delivered to the patient,approximately 6% to 9% of the nominal dose is delivered to the lungs.

The invention also features a kit for treating respiratory diseases, thekit including a budesonide composition in a sealed container, thecomposition including 0.05 mg to 15 mg budesonide and a solvent, and alabel indicating administration by nebulization in a continuing regimenat a frequency of not more than once per day.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention, e.g., treatment ofchildhood asthma, will be apparent from the following description andfrom the claims.

DETAILED DESCRIPTION

The invention is a convenient yet highly effective method of treatingasthma involving not more than one administration per day in acontinuing dosage regimen. This new method represents a significantadvantage, particularly in infants and young children in which it isfrequently difficult to achieve compliance with treatments involvingmore frequent administrations. Such treatments can involve the use ofportable propellant-based inhalers which a young child can either useimproperly, lose, or be embarrassed to use in front of his or her peers.Once a day or less frequent treatments are cost effective and result inan improved quality of life. In general, a patient (or a patient'sfamily) can choose a time of administration that is convenient for them.

In infants, standard inhalation devices are technically difficult touse. The fact that in the new method the drug can be delivered by a maskapplied over the infant's nose and mouth obviates this problem. Inaddition, in using the nebulizer for administration, the drug isconstantly pumped into the face mask. Thus, effective drug delivery doesnot require constant and deep inhalation. This aspect of the treatmentis also advantageous in, for example, incapacitated or neurologicallyimpaired patients.

Two randomized, double-blind, placebo-controlled, twelve-week studiesassessed the efficacy and safety of budesonide in children six months toeight years of age who had persistent asthma that was not effectivelycontrolled by non-GCS therapies. The budesonide suspended in a solvent(or a placebo) was administered once per day by a nebulizer connected toa compressor. This treatment resulted in statistically significantimprovements in asthma symptoms and a decrease in the number of days inwhich auxiliary bronchodilator medication was used. Furthermore, therewere no significant differences between treatment groups in the type,incidence, or severity of adverse events. There were also no apparentdifferences between the groups in changes observed in physicalexaminations, clinical laboratory tests, or oropharyngeal or nasalfungal cultures. Measurement of adrenocorticotropic hormone(ACTH)-induced plasma cortisol levels showed no evidence ofhypothalamus-pituitary-adrenal (HPA)-axis suppression by budesonideafter twelve weeks of treatment. In summary, these results demonstratedboth the efficacy and safety of budesonide when administered to childrenonce per day.

After it has been taken up by airway cells, budesonide forms conjugates(esters) with long-chain fatty acids such as oleic acid. Unlike freebudesonide, the budesonide conjugates are inactive as they do not bindto the GCS receptor. However, the conjugation of budesonide is areversible process. As the concentration of free budesonide in theairway cells falls, the conjugates undergo lipolysis, and further freebudesonide is produced, thus maintaining the level available forreceptor binding. Intracellular conjugated budesonide thus acts as a“depot” of free budesonide in the airway cells, prolonging the localeffect of the compound. This proposed mechanism of action is exemplary;the invention is not limited by any particular mechanism of action.

Methods of Treating Respiratory Diseases

The invention features a new method for treating a patient sufferingfrom a respiratory disease using the drug budesonide which isadministered to the patient not more frequently than once per day. Itcan be delivered, for example, once a day, once every 1.5 days, onceevery 2 days, once every 3 days, once a week, once every two weeks, oronce a month. Treatment is in a continuing regimen for as long asrequired.

The drug can be delivered dispersed in a solvent, e.g., in the form of asolution or a suspension. It can be suspended in an appropriatephysiological solution, e.g., physiological saline or a bufferedsolution containing 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrouscitric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water soas to achieve a pH of about 4.0 to 5.0. The budesonide suspension canmade, for example, from micronized budesonide.

The therapeutic suspensions can also contain one or more excipients.Excipients are well known in the art and include buffers (e.g., citratebuffer, phosphate buffer, acetate buffer and bicarbonate buffer), aminoacids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g.,serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol,and glycerol. Solutions or suspensions can be encapsulated in liposomesor biodegradable microspheres.

The budesonide suspension is provided in a substantially sterile formby, for example, dry-heating the budesonide powder for 2 to 6 hours at90° C. to 150° C. and employing sterile manufacture for the rest of theprocess. This involves production and sterilization by filtration of thebuffered solvent solution used for the suspension, aseptic suspension ofthe budesonide in the sterile buffered solvent solution, and dispensingof the suspension into sterile receptacles by methods familiar to thoseof ordinary skill in the art. This process results in a sterilityassurance of 6 as required by the Food and Drug Administration of theU.S. government.

The route of administration is intrapulmonary and the drug is deliveredin a nebulized composition by, for example, a nebulizer connected to acompressor (e.g., the Pari LC-Jet Plus® nebulizer connected to a PariMaster® compressor manufactured by Pari Respiratory Equipment, Inc.,Richmond, Va.).

Patients are those suffering from a respiratory disease. Relevantrespiratory diseases include inflammatory airway diseases, croup, andbronchopulmonary dysplasia. Examples of inflammatory airway diseasesinclude asthma, COPD and bronchiolitis.

Patients can be of either sex. They can be treated by the new method atany age from birth. They can, for example be treated as early as thirtyminutes after birth. The patients can also much older, e.g., twelvemonths, two years, four years, ten years, forty years, or even seventyyears of age, or older. Patients can be six months to five or eightyears old.

Doses of budesonide can be the same, or can be varied, for patients ofall age groups and all sizes and weights. When administered as anebulized suspension, the dose can be, e.g., 0.05 mg to 15 mg, 0.1 mg to2.0 mg, or 0.25 mg to 1.0 mg budesonide per administration. Eveningadministration can result in better control of nocturnal and earlymorning symptoms which are frequent problems in asthma. If excessbudesonide is used in a single administration, it is unlikely thatharmful effects will occur.

Nebulizable budesonide is provided, for example, as single dose units(e.g., sealed plastic containers or vials) packed in foil envelopes.Each vial contains a unit dose (e.g., 0.25 mg, 0.5 mg, or 1.0 mg) ofmicronized budesonide suspended in a volume, e.g., 2 ml, of solvent. Theunit dose or, if desired and directed by a physician, a fraction of theunit dose is added to the nebulizer. Patients should rinse out theirmouths with water after administration of each dose.

Where diseases other than asthma are to be treated with solventdispersed budesonide, optimal doses can be established by methodsfamiliar to those in the art, e.g., methods analogous to those describedin Examples 1 and 2. Doses, for example, for COPD, bronchiolitis, croup,and bronchopulmonary dysplasia, as in asthma, can generally be 0.05 to15 mg, 0.1 mg to 2.0 mg, or 0.25 mg to 1.0 mg budesonide peradministration.

The following examples are meant to illustrate, not limit, theinvention.

EXAMPLES Example 1 A Phase III Study of Three Dose Levels of Once-A-DayBudesonide Nebulizing Suspension and Placebo in Asthmatic Children

Objectives

The objectives of the study were to compare the relative efficacy andsafety of a nebulizing suspension of budesonide (containing 0.25 mg, 0.5mg, or 1.0 mg of budesonide per dose), administered once a day, inpediatric asthmatic patients aged six months to eight years.

Methodology

This was a multicenter, randomized double-blind, placebo-controlled,parallel-group study.

Number of Subjects

The total number of patients in the study was 359, the number analyzedfor efficacy was 358 and the number analyzed for safety was 359.

Diagnoses and Main Criteria for Inclusion

Patients were asthmatic children who had not been treated with steroidsin the 30 days prior to initiation of the study treatment. They wereaged six months to eight years of age and had a diagnosis of asthma asdefined by the National Institutes of Health of the U.S. Department ofHealth and Human Services, including: (a) exacerbations of cough and/orwheezing on a frequent basis, including nocturnal asthma, withinfrequent severe exacerbations during the last six months; (b) dailyuse of at least one chronic asthma medication with periodic use ofbreakthrough medication for at least three months prior to Visit 1; (c)basal FEV₁ (forced expiratory volume, in liters per second) of ≧50% ofpredicted, and reversibility of ≧15% at 15±5 minutes after a standarddose of inhaled bronchodilator for patients old enough to performconsistent pulmonary function tests (PFT).

Test Drug, Doses, and Mode of Administration

Budesonide was administered once per day as a nebulized suspension, at0.25 mg, 0.5 mg, or 1.0 mg per administration, via a Pari LC-Jet Plus®nebulizer connected to a Pari Master® compressor (Pari RespiratoryEquipment, Inc., Richmond, Va.) with a face mask or a mouth piece. Theplacebo was the solvent used for the budesonide suspension (0.1 mgdisodium edetate, 8.5 mg NaCl, 0.2 mg polysorbate, 0.28 mg anhydrouscitric acid, and 0.5 mg sodium citrate per 1 ml water) but withoutbudesonide.

Efficacy Variables

Primary efficacy variables were mean changes from baseline in daytimeand nighttime asthma symptom scores over the 12 week treatment phase.The symptom scores are based on the subjective evaluation by thepatients or their parents based on a 0-3 rating system in which 0=nosymptoms, 1=mild symptoms, 2=moderate symptoms, and 3=severe symptoms.

Secondary efficacy variables were: (a) patient outcomes, including theproportion of patients who were discontinued from the study for anyreason and the proportion of patients who were discontinued from thisstudy due to worsening asthma; (b) the number of days breakthrough(bronchodilator) medication was used; (c) spirometry test variables,including FEV₁, FEF₂₅₋₇₅ (forced expiratory flow during the middle halfof the forced vital capacity in liters per second) and FVC (forced vitalcapacity in liters), performed at clinic visits in the subset ofpatients capable of performing spirometry testing; (d) PEF (peakexpiratory flow in liters per minute) measured daily in the morning andevening in the subset of patients capable of performing PEF testing; (e)changes in health status measurements, including the Modified FunctionalStatus II Scale Child Health Status Scale and the RAND General HealthIndex; and (f) differences in asthma-related health care utilization andindirect health care costs.

Safety Variables

Safety variables were: (a) reported adverse effects that could be due tothe drug; (b) morning basal and post-ACTH-simulation effects on plasmacortisol levels (HPA-axis function); and (c) changes in physicalexaminations, vital signs, and clinical laboratory tests, includingoropharyngeal and nasal fungal cultures.

Statistical Methods

Analysis of variance was used to compare differences between treatmentgroups for all efficacy variables, with the exception of patientoutcomes, which were analyzed using Fisher's exact test. Analysis ofvariance was also used for morning basal and post-ACTH-simulationeffects on plasma cortisol levels. Descriptive statistics were used topresent all other safety data.

Efficacy Results

Results of nighttime and daytime asthma symptom scores, and the numberof days of use of breakthrough medication are presented in Table 1. Dataare expressed as the adjusted mean change from baseline over the 12-weektreatment phase, all patients treated, last value carried forward(*p≦0.050, **p≦0.010, and ***p≦0.001 versus placebo (PBO); “n” is numberof patients). Thus improvements are indicated by negative values ofthese variables. Patients in the 0.25 mg, 0.5 mg, and 1.0 mg per daytreatment groups showed statistically significant improvements in theirasthma symptom scores and fewer days of bronchodilator therapy whencompared to placebo.

The total proportion of patients who were discontinued from the placebogroup (28%) was greater than that for the budesonide groups (19%, 24%,and 14% for the 0.25 mg, 0.5 mg and 1.0 mg groups, respectively); theproportion in the placebo group was significantly different from that inthe 1 mg group (p=0.020). The proportion of patients in the placebogroup discontinuing due to worsening asthma (23%) was also greater thanfor the budesonide groups (14%, 17% and 13% of patients in the 0.25 mg,0.5 mg and 1.0 mg groups, respectively). These differences were notstatistically significant. Since the study was double-blind, patientswith worsening asthma in all study groups were discontinued in order toensure that the placebo patients with worsening asthma could receivealternate therapy. TABLE 1 Comparison of the Efficacy of Three DifferentDoses of Budesonide Budesonide Dose Variable PBO 0.25 mg 0.5 mg 1.0 mgAsthma scores: (n = 92) (n = 91) (n = 82) (n = 93) Nighttime −0.16−0.49*** −0.42** −0.42** Daytime −0.26 −0.57** −0.46* −0.50* Days of useof −4.19 −6.26* −5.31* −5.98* bronchodilator FEV₁(L) −0.07 −0.01 0.03*0.03* (n = 38) (n = 29) (n = 28) (n = 33) Morning PEF (L/min) 7.1 14.46.5 10.9 (n = 55) (n = 44) (n = 41) (n = 55)

Improvements in lung function were associated with budesonide treatmentin the subset of patients capable of performing PFT (Table 1).Clinically and statistically significant improvements in FEV₁ wereobserved in the 0.5 mg and 1.0 mg budesonide treatment groups comparedto placebo. Improvements in FVC, FEF₂₅₋₇₅ and morning and evening PEFwere also observed in the budesonide groups, with FVC improvements inthe 0.5 mg treatment group being statistically significant compared toplacebo.

Patients in the 0.25 mg budesonide treatment group had clinically andstatistically significant improvements compared to placebo in healthstatus scores at weeks 4 and 12 for the FS-II(R) General score.Improvements were also seen in the FS-II(R) Specific scores, withstatistical significance compared to placebo for the 0.5 mg budesonidegroup at week 12. Patients in all the budesonide treatment groups alsodemonstrated improvements in the RAND General Health Index scorescompared to placebo. In addition, patients in the budesonide treatmentgroups showed improvements in health care utilization and fewerasthma-related phone calls to physicians. Variables associated withindirect costs, including days absent from school, and days in whichroutine was interrupted also showed improvement.

Safety Results

There were no deaths reported during the study. There were a total of 10serious adverse events in 8 of the patients in the study. There were 4discontinuations due to adverse events.

This study showed that children aged between six months and eight yearswith asthma, receiving budesonide at the three doses once a day for 12weeks, had no clinically relevant differences in the frequency ofclinically significant changes in nasal or oral fungal cultures betweentreatment groups. There were no clinically relevant differences betweentreatment groups in vital signs or physical examination differences.

Assessments to determine the possible effects of study treatment onbasal and post-ACTH-stimulated plasma cortisol levels showed nosignificant differences between active treatment groups and placebo frombaseline to week 12. Thus, there was no evidence of HPA-axis suppressionby budesonide at the three doses studied. ACTH production is stimulatedby injection (intravenous for young children and intramuscular forinfants) of corticotropin one hour before morning blood sampling.

CONCLUSION

This study in infants and young children aged six months to eight yearswith asthma demonstrated that the budesonide containing suspensionsignificantly improved both nighttime and daytime asthma symptomscompared to placebo. Efficacy was further supported by a decrease in theuse of short-acting bronchodilators and by an increase in FEV₁ (in thesubgroup of patients who could consistently perform spirometry).Furthermore, there were no differences between treatments inspontaneously reported adverse events or response to ACTH-stimulationtests, strongly supporting the safety of 0.25 mg to 1.0 mg budesonidecontaining suspension administered once per day. All three doses ofbudesonide in suspension were more efficacious than placebo, but therewere no differences between the three active treatments.

In summary, budesonide in a nebulized suspension, administered at 0.25mg, 0.5 mg, or 1.0 mg once daily, is an effective and well-toleratedtreatment for non-steroid-treated infants and young children between sixmonths and eight years of age.

Example 2 A Phase III Study of Four Dose Regimens of Budesonide in aNebulizing Suspension and Placebo in Asthmatic Children Aged Eight Yearsand Younger

Objectives

The objectives of the study were to compare the relative efficacy andsafety of budesonide in a nebulizing suspension (0.25 mg administeredonce a day (QD), 0.25 mg administered twice per day (BID), 0.5 mg BID or1.0 mg QD) in pediatric asthmatic patients aged six months to eightyears.

Methodology

This was a multicenter, randomized double-blind, placebo-controlled,parallel-group study.

Number of Subjects

The number of patients in the study was 481, the number analyzed forefficacy was 471, and the number analyzed for safety was 480.

Diagnoses and Main Criteria for Inclusion

Patients were mild to moderate asthmatic children aged six months toeight years of age with a diagnosis of asthma as defined by the NationalInstitutes of Health of the U.S. Department of Health and HumanServices, including: (a) exacerbations of cough and/or wheezing on afrequent basis, including nocturnal asthma, with infrequent severeexacerbations during the last six months; (b) daily use of at least onechronic asthma medication (which could have been an inhaled GCS) withperiodic use of breakthrough medication for at least three months priorto Visit 1; and (c) basal FEV₁ of ≧50% of predicted and reversibility of≧15% at 15±5 minutes after a standard dose of inhaled bronchodilator forpatients capable of performing consistent PFTs.

Test Drug, Doses and Mode of Administration

Budesonide was administered once per day as a nebulized suspension, atthe indicated doses (0.25 mg QD, 0.25 mg BID, 0.5 mg BID or 1.0 mg QD)by the mode described in Example 1.

Efficacy Variables

Primary efficacy variables were mean changes from baseline in daytimeand nighttime asthma symptom scores over the 12-week treatment phase.The symptom scores were obtained as in Example 1.

Secondary efficacy variables were: (a) the number of days breakthrough(bronchodilator) medication was used; (b) spirometry test variables,including FEV₁, FEF₂₅₋₇₅, and FVC performed at clinic visits in thesubset of patients capable of performing spirometry testing; (c) PEFmeasured daily in the morning and evening in the subset of patientscapable of performing PEFs; and (d) proportion of patientdiscontinuations from the study.

Safety Variables

Safety variables were: (a) reported adverse events that could be due tothe drug; (b) morning basal and post-ACTH-simulation effects on plasmacortisol levels (HPA-axis function) in a subset of patients; and (c)changes in physical examinations, vital signs and clinical laboratorytests, including oropharyngeal and nasal fungal cultures.

Statistical Methods

Analysis of variance was used to compare differences between treatmentgroups for all efficacy variables, with the exception of patientdiscontinuations from the study, which was analyzed using Fisher's exacttest. Analysis of variance was also used for morning basal andpost-ACTH-simulation effects on plasma cortisol levels. Descriptivestatistics were used to present all other safety data.

Efficacy Results

A total of 481 patients were included in the study. Patient demographieswere similar for the four treatment groups. Males constituted 64.4% ofthe randomized patients. 80.5% of the patients were Caucasian, with therest being Blacks (13.7%), Hispanics (3.7%), and other ethnic groups(2.1%). The mean age, weight, and height at screening were 55±26.3months (range 7-108 months), 43.1±16.3 pounds (19.5±7.4 kg) and106.5±16.4 cm, respectively. The mean duration of asthma at screeningwas 34.2±22.9 months. The mean nighttime and daytime asthma symptomscores at baseline were 1.22±0.62 and 1.28±0.50, respectively. A totalof 164 (34.1%) of the patients were capable of performing PEF maneuvers.The mean morning and evening PEF values at baseline for these patientswere 159.9±43.0 and 168.3±43.1 L/min, respectively.

A total of 471 patients were evaluated for efficacy (all patientstreated). Efficacy results are shown in Table 2. Data are expressed asthe adjusted mean change from baseline over the 12-week treatment phase,all patients treated, last value carried forward (*p≦0.050; **p≦0.010and ***p≦0.001, versus placebo; “n” is the number of patients). TABLE 2COMPARISON OF THE EFFICACY OF BUDESONIDE ADMINISTERED ONCE AND TWICE PERDAY Budesonide Dose Placebo 0.25 mg QD 0.25 mg BID 0.5 mg BID 1.0 mg QDNighttime Asthma −0.13 −0.28 −0.49*** −0.42** −0.40** Symptom Score (n =92) (n = 93) (n = 97) (n = 96) (n = 93) Daytime Asthma −0.19 −0.28−0.40* −0.46** −0. 37* Symptom Score (n = 92) (n = 92) (n = 97) (n = 96)(n = 93) Number of Days −2.36 −4.39* −5.22*** −4.92** −4.38* Use of (n =92) (n = 93) (n = 97) (n = 96) (n = 93) Breakthrough Medication MorningPEF −0.2 10.9 23.0** 24.8** 17. 1* (n = 32) (n = 32) (n = 34) (n = 29)(n = 34) Evening PEF  1.9 16.8* 19.2* 21.0** 14.1 (n = 32) (n = 32) (n =34) (n = 29) (n = 34) FEV₁  0.04  0.07  0.03  0.17*  0.11 (n = 28) (n =31) (n = 33) (n = 29) (n = 34)

The data demonstrated that 0.25 mg BID, 0.5 mg BID, and 1.0 mg QDbudesonide provided statistically significant and clinically relevantimprovement in patient nighttime and daytime asthma symptoms compared toplacebo. Furthermore, patients receiving all four budesonide regimenshad statistically significant and clinically relevant decreases in thenumber of days of breakthrough medication use compared to placebo.

In those children who could perform PEF assessments, statisticallysignificant improvements in morning PEF from baseline to weeks 0-12 wereseen in the 0.25 mg BID, 0.5 mg BID, and 1.0 mg QD mg budesonidetreatment groups compared to placebo. Statistically significantimprovements in evening PEF from baseline to weeks 0-12 were seen in the0.25 mg QD, 0.25 mg BID, and 0.5 mg QD budesonide nebulizing suspensiontreatment groups compared to placebo. In those patients able to performPFTs consistently, the lung function measures of FEV₁, FVC, and FEF₂₅₋₇₅improved clinically for all the budesonide treatment groups compared toplacebo, with statistical significance achieved in FEV₁ and FVC for thebudesonide 0.5 mg BID treatment group.

The total proportion of patients who were discontinued from the placebogroup (39%) was greater than that for the budesonide treatment groups(21%, 21%, 19% and 31% for the 0.25 mg QD, 0.25 mg BID, 0.5 mg BID and1.0 mg QD groups, respectively); the proportion in the placebo group wassignificantly different from those in the 0.25 mg QD, 0.25 mg BID, and0.5 mg BID budesonide treatment groups (p<0.01). The proportion ofpatients in the placebo group discontinuing due to worsening asthma(26.3%) was also greater than for budesonide treatment groups (16.0%,13.1%, 15.3% and 21.1% of patients for the 0.25 mg QD, 0.25 mg BID, 0.5mg BID, and 1.0 mg QD groups, respectively; these differences werestatistically significant for the 0.25 mg BID budesonide versus placebocomparison, p=0.029).

Safety Results

One randomized patient never took the study drug and therefore was notincluded in the safety analysis. There were no deaths reported duringthe study. A total of 13 serious adverse events in 13 patients werereported during the treatment phase, all recovering completely withoutsequelae (4, 4, 2, 1, and 4 serious adverse events in the placebo, 0.25mg QD, 0.25 mg BID, 0.5 mg BID, and 1.0 mg QD groups, respectively). Atotal of six patients were discontinued due to adverse effects (2, 1, 1,and 2 patients in the placebo and the 0.25 mg BID, 0.5 mg BID, and 1.0mg QD groups, respectively). One of the adverse events leading todiscontinuation from the treatment phase was judged by the investigatorto be of probable relationship to the study treatment. The patient wasin the 1.0 mg QD group and developed laryngismus.

The study showed that children aged six months to eight years withasthma, receiving budesonide as a nebulized suspension at 0.25 mg QD,0.25 mg BID, 0.5 mg BID, or 1.0 mg QD for 12 weeks had no clinicallyrelevant differences in the type, incidence or severity of adverseevents compared to placebo. There were also no apparent differences inthe number of patients with clinically significant changes in nasal ororal fungal cultures between treatment groups. There were no clinicallyrelevant differences between treatment groups in vital signs or physicalexamination outcomes.

Assessments to determine the possible effects of study treatment onbasal and post-ACTH-stimulated plasma cortisol levels showed nosignificant differences between the active treatment groups and placebofrom baseline to week 12. Thus, there was no evidence of HPA-axissuppression by budesonide in a nebulized suspension when administered inthe four regimens studied.

CONCLUSION

Budesonide in a nebulized suspension, when administered in regimens of0.25 mg QD, 0.25 mg BID, 0.5 mg BID, or 1.0 mg QD, was effective andwell tolerated by infants and young children aged between six months andeight years with asthma who had previously been or not been treated withinhaled GCS.

OTHER EMBODIMENTS

It is understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1.-30. (canceled)
 31. A method of treating a patient suffering from arespiratory disease, the method comprising administering to the patienta nebulized dose of a budesonide solution in a continuing regimen at afrequency of not more than once per day, wherein the respiratory diseaseis asthma or chronic obstructive pulmonary disease.
 32. The method ofclaim 31, wherein the frequency is once and only once per day.
 33. Themethod of claim 31, wherein the frequency is once and only once everyother day.
 34. The method of claim 31, wherein the patient is one day tofifteen years old.
 35. The method of claim 31, wherein the patient isone month to eight years old.
 36. The method of claim 31, wherein thepatient is six months to five years old.
 37. The method of claim 31,wherein the budesonide solution contains 0.05 mg to 15 mg budesonide.38. The method of claim 31, wherein the budesonide solution contains 0.1mg to 2.0 mg budesonide.
 39. The method of claim 31, wherein thebudesonide solution contains 0.25 mg to 1.0 mg budesonide.
 40. Themethod of claim 31, wherein the budesonide solution further compriseswater and 0.05 mg to 0.15 mg sodium edetate, 8.0 mg to 9.0 mg sodiumchloride, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrouscitric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water.41. The method of claim 31, wherein budesonide is the only activeingredient in the budesonide solution.
 42. The method of claim 31,wherein the administration is in the evening.
 43. A kit for treatingrespiratory diseases, the kit comprising (a) a budesonide solution in asealed container, the solution containing 0.05 mg to 15 mg budesonideand a solvent, and (b) a label indicating administration by nebulizationin a continuing regimen at a frequency of not more than once per day.44. The kit of claim 43, wherein the solution contains 0.25 mgbudesonide.
 45. The kit of claim 43, wherein the solution contains 0.5mg budesonide.
 46. The kit of claim 43, wherein the solution contains1.0 mg budesonide.
 47. The kit of claim 43, wherein the solutioncontains 2 ml of solvent.
 48. The kit of claim 43, wherein the frequencyis once and only once per day.
 49. The kit of claim 43, wherein thefrequency is once and only once every other day.
 50. The kit of claim43, wherein the respiratory disease is selected from the groupconsisting of an inflammatory airway disease, croup, andbronchopulmonary dysplasia.
 51. The kit of claim 43, wherein therespiratory disease is asthma.
 52. The kit of claim 43, wherein therespiratory disease is chronic obstructive pulmonary disease orbronchiolitis.
 53. The kit of claim 43, wherein the administration is inthe evening.
 54. The kit of claim 43, wherein the patient is one day tofifteen years old.
 55. The kit of claim 43, wherein the patient is onemonth to eight years old.
 56. The kit of claim 43, wherein the patientis six months to five years old.
 57. The kit of claim 43, whereinbudesonide is the sole active ingredient in the solution.